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GeneBe

4-3518035-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_002337.4(LRPAP1):c.750T>C(p.Ala250=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,601,412 control chromosomes in the GnomAD database, including 19,842 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.15 ( 1808 hom., cov: 33)
Exomes 𝑓: 0.15 ( 18034 hom. )

Consequence

LRPAP1
NM_002337.4 splice_region, synonymous

Scores

2
Splicing: ADA: 0.00001405
2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.34
Variant links:
Genes affected
LRPAP1 (HGNC:6701): (LDL receptor related protein associated protein 1) This gene encodes a protein that interacts with the low density lipoprotein (LDL) receptor-related protein and facilitates its proper folding and localization by preventing the binding of ligands. Mutations in this gene have been identified in individuals with myopia 23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 4-3518035-A-G is Benign according to our data. Variant chr4-3518035-A-G is described in ClinVar as [Benign]. Clinvar id is 3059677.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-3518035-A-G is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-1.34 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LRPAP1NM_002337.4 linkuse as main transcriptc.750T>C p.Ala250= splice_region_variant, synonymous_variant 5/8 ENST00000650182.1
LRPAP1NR_110005.2 linkuse as main transcriptn.713T>C splice_region_variant, non_coding_transcript_exon_variant 5/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LRPAP1ENST00000650182.1 linkuse as main transcriptc.750T>C p.Ala250= splice_region_variant, synonymous_variant 5/8 NM_002337.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.148
AC:
22487
AN:
152016
Hom.:
1806
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.152
Gnomad AMI
AF:
0.246
Gnomad AMR
AF:
0.142
Gnomad ASJ
AF:
0.222
Gnomad EAS
AF:
0.000772
Gnomad SAS
AF:
0.0831
Gnomad FIN
AF:
0.114
Gnomad MID
AF:
0.212
Gnomad NFE
AF:
0.162
Gnomad OTH
AF:
0.187
GnomAD3 exomes
AF:
0.130
AC:
31428
AN:
242158
Hom.:
2444
AF XY:
0.130
AC XY:
17184
AN XY:
131828
show subpopulations
Gnomad AFR exome
AF:
0.151
Gnomad AMR exome
AF:
0.0958
Gnomad ASJ exome
AF:
0.223
Gnomad EAS exome
AF:
0.000662
Gnomad SAS exome
AF:
0.0861
Gnomad FIN exome
AF:
0.115
Gnomad NFE exome
AF:
0.164
Gnomad OTH exome
AF:
0.149
GnomAD4 exome
AF:
0.152
AC:
220728
AN:
1449280
Hom.:
18034
Cov.:
32
AF XY:
0.151
AC XY:
108393
AN XY:
719852
show subpopulations
Gnomad4 AFR exome
AF:
0.153
Gnomad4 AMR exome
AF:
0.102
Gnomad4 ASJ exome
AF:
0.228
Gnomad4 EAS exome
AF:
0.000380
Gnomad4 SAS exome
AF:
0.0866
Gnomad4 FIN exome
AF:
0.117
Gnomad4 NFE exome
AF:
0.164
Gnomad4 OTH exome
AF:
0.150
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.148
AC:
22512
AN:
152132
Hom.:
1808
Cov.:
33
AF XY:
0.143
AC XY:
10653
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.152
Gnomad4 AMR
AF:
0.141
Gnomad4 ASJ
AF:
0.222
Gnomad4 EAS
AF:
0.000774
Gnomad4 SAS
AF:
0.0836
Gnomad4 FIN
AF:
0.114
Gnomad4 NFE
AF:
0.162
Gnomad4 OTH
AF:
0.184
Alfa
AF:
0.155
Hom.:
624
Bravo
AF:
0.153
Asia WGS
AF:
0.0470
AC:
165
AN:
3478
EpiCase
AF:
0.175
EpiControl
AF:
0.173

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

LRPAP1-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 30, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.92
Cadd
Benign
0.034
Dann
Benign
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000014
dbscSNV1_RF
Benign
0.0
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs13325; hg19: chr4-3519762; COSMIC: COSV56346174; API